Compositions and methods for reducing the risk of epileptic occurrence and/or for treatment of seizure disorders

ABSTRACT

The present invention relates to compounds and compositions useful for reducing the risk of epileptic occurrences and/or for alleviating epileptic phenomena in patients. In accordance with the invention, the compounds and compositions have at least the following two components: a) vitamin B6-based component selected from pyridoxal, pyridoxamine, pyridoxine, their pharmaceutically acceptable functional derivatives and salts; and b) at least one antiepileptic drug (AED) or anticonvulsive, neuro-protective drug or nootrope compound or moiety. The invention further relates to methods for preventing epileptic episodes and for alleviating epileptic episodes, as well as methods for reducing side effects of antiepileptic drugs.

FIELD OF THE INVENTION

The present invention relates to compositions and methods of using suchcompositions for the treatment and prevention of epilepsy and relateddisorders.

BACKGROUND OF THE INVENTION

Epilepsy is one of the most common chronic neurological disorders. Thedisease is characterized by recurrent seizures, which originate fromabnormal and excessive activity of cerebral neurons and result in aparoxysmal disorganization of brain function. Types of epilepsy includepartial (symptomatic) and generalized idiopathic seizures. Partialepilepsy is “localization related” and originates in a limited area ofthe brain. The generalized form of epilepsy is not caused by a specificbrain lesion or disease, other than a possible genetic propensity togenerate seizures. Generalized, or grand mal, seizures includetonic-clonic seizures, in which the entire body undergoes convulsions.Left untreated, epilepsy can degenerate into status epilepticus, apotentially fatal neurological emergency [Antiepileptic Drugs; eds. R.H. Levy, R. H. Mattson and B. S. Meldrum; 4th Edition, Raven Press, NY,N.Y.; Aicardi. Epilepsy in children. 2nd edition. New York: Raven Press,1994: 18-43]. Idiopathic epilepsy appears to be a heritable disorderthough little is known about the precise genetic or biochemical defectsinvolved (Andermann In Genetic Basis of the Epilepsies, eds. Anderson VE, Hauser W A, Penry J K, Sing C F. New York: Raven Press 1982: 355-74;Anderson E V, Hauser W A. Genetics. In: Dam M, Gram L, ed. ComprehensiveEpileptology. New York: Raven Press 1990:57-76). Recent research hasindicated the possibility of genetic predisposition to the developmentof localization-related epilepsy, in particular post-traumatic epilepsy.In this type of epilepsy, a head injury is the resolving exogenousfactor inducing the disease with a low penetration of the pathologicalhereditary factor.

Over 53 million people worldwide suffer from epilepsy, with 2.5 millionwho have had, or who will have seizures at some point in the U.S. alone.Epilepsy primarily affects children and young adults. Almost 50% of newepilepsy cases occur prior to age 25. About 28% of epileptic patientshave intractable epilepsy that is resistant to antiepileptic treatment.A wide spectrum of antiepileptic drugs is used for epilepsy treatment[Antiepileptic Drugs; eds. R. H. Levy, R. H. Mattson and B. S. Meldrum;4th Edition, Raven Press, NY, N.Y.; Aicardi, Epilepsy in children, 2dEdition, Raven Press, 1994]. Nevertheless, a goal, that was expressed 10years ago (Drugs and Market Development, 1992, v.2, N3), namely todevelop antiepileptic drugs (AEDs) which are equally effective yet lesstoxic than the AEDs currently on the market, has not been accomplished.

One specific form of epilepsy, known as “pyridoxine-dependent epilepsy”has been described as a rare (1:100 000) autosomal recessive geneticdisorder that causes severe convulsions with subsequent mentalretardation in neonates and infants (Hunt et al. Pediatrics 1954;13:140; Rosenberg In: Medical Genetics McKusic V A, ed. 1995: 73-8;Shideler Am. J. Med. Technol. 1983; 49:17-22 Scriver and HutchisonPediatrics 1963; 31:240-50).

It was reported in the art that pyridoxine-dependent epilepsy can betreated by administration of pyridoxine (Aicardi, Epilepsy in children,2d Edition, Raven Press 1994; Epilepsy Problems Solving in ClinicalPractice; eds. D. Schmidt, S. C. Schachter; Martin Dunitz, 2000). Theliterature, however, suggests that medicinal method of treatingpyridoxine-dependent epilepsy is unsuitable for the treatment of otherforms of epilepsy.

Vitamin B6 (pyridoxine) plays a crucial role in the metabolism of aminoacids, proteins, carbohydrates, lipids, hormones and neuromediators(Lumeng L, Li T K. Mammalian vitamin B₆ metabolism: regulatory role ofprotein-binding and the hydrolysis of pyridoxine 5′-Phosphate in storageand transport. In: G. P. Tryfiates, ed. Vitamin B₆ , Metabolism and Rolein Growth. Food & Nutrition Press, Inc., Westport, Conn. 06880 USA,1980: 27-51). The active form, pyridoxal-5′-phosphate (PLP), is thecoenzyme of a large number of enzymes in mammalian tissues, includingtransaminases, decarboxylases and lyases, etc. Neurotransmitters (e.g.dopamine, norepinephrine, serotonin, tyramine, tryptamine, taurine, GABA(γ-aminobutyric acid), and indirectly acetylcholine) are alsosynthesized and/or metabolized by PLP-dependant enzymatic reactions (forreviews:Metzler, Biochemistry, Academic Press, 1977; Ebadi M.,Regulation and function of pyridoxine phosphate in CNS. Neurochem.Int1981,3,181-206; Leklem 1988 Vitamin B6 metabolism and function inhumans. In: Clinical and physiological Application of vitamin B6 (Leklem& Reynolds eds.,) Alan R. Liss, NY, 1988; Shideler Ch. Vitamin B6: AnOverview. Am. J. Med. Technol. 1983; 49:17-22).

SUMMARY OF THE INVENTION

There is provided in accordance with a preferred embodiment of theinvention a composition for reducing the risk of epileptic occurrencesand/or for alleviating epileptic phenomena in patients. In one preferredembodiment of the invention, the composition comprises a chemicalcompound consisting of a vitamin B6 moiety which is chemically linked toanother chemical moiety selected from the group of anti-epileptic drugs(AEDs) and anticonvulsive, neuroprotective, neurotransmitter andnootrope moieties. Preferably, the dosage of the composition is suchthat neither the vitamin B6 moiety nor the AED moiety/anticonvulsivemoiety is present at more than the safe maximum dosage of that moiety.Such a compound may be represented by the formula:

wherein R′ represents the AED moiety or anticonvulsive, neuroprotective,neurotransmitter, or nootrope moiety and R is selected from the groupconsisting of —CH₂OH, —CHO and —CH₂NH₂; and pharmaceutically acceptablesalts thereof.

In another preferred embodiment of the invention, the compositioncomprises a physical mixture of:(a) a vitamin B6 compound having the formula:

wherein R is selected from the group consisting of —CH₂OH, —CHO and—CH₂NH₂, and the vitamin B6 compound is employed in a single dosage nogreater than its maximum safe dosage for single administration and itsdaily dose is no greater than maximum safe daily dosage, and(b) an AED or anticonvulsive, neuroprotective drug, or nootropecompound, the AED or compound being employed in a dosage no greater thanits maximum safe dosage for single administration, and its daily dose isno greater than maximum safe daily dosage.

In accordance with another preferred embodiment of the invention, acomposition as set forth above is administered to a patient in such amanner that both the vitamin B6 compound and the AED, anticonvulsive,neuroprotective drug or nootrope compound are present in the patient ina single formulation.

The present invention also provides a method of treatment in which thereis administered to patient in need of treatment at least one substanceselected from the group consisting of pyridoxal, pyridoxamine andpyridoxine, their pharmaceutically acceptable functional derivatives andsalts of any of these substances, in an amount which is equivalent tofrom about 2 to about 500 times the recommended daily dietary allowanceof pyridoxine. Such at least one substance may be co-administered withat least one AED, anticonvulsive, neuroprotective drug or nootropecompound.

The present invention also provides a pharmaceutical composition whichcomprises a mixture, preferably an admixture, of at least the followingcomponents (i), (ii) and (iii), namely:

-   -   (i) at least one substance selected from the group consisting of        pyridoxal, pyridoxamine and pyridoxine, their pharmaceutically        acceptable functional derivatives and salts of any of these        substances;    -   (ii) at least one AED or anticonvulsive, neuroprotective drug or        nootrope compound; and    -   (iii) at least one pharmaceutically acceptable carrier, diluent,        or excipient.

In a preferred embodiment of the invention, the mixture or admixture,and/or the individual components thereof, may be microencapsulated,using conventional micro encapsulation techniques, such as are disclosedin U.S. Pat. No. 6,156,347, the contents of which are incorporatedherein by reference. Liposomes may also be employed formicroencapsulation of the admixture or components thereof, as is knownin the art.

As stated above, in one aspect the invention relates to theadministration to a human subject of an amount of at least one of adefined group of substances in an amount not more than 500 mg/day, i.e.equivalent to about 2 to about 500 times the recommended daily dietaryallowance of pyridoxine. In the present specification and claims, therecommended daily dietary allowance of pyridoxine means such allowancepublished by the Food and Nutrition Board of the National Academy ofSciences—National Research Council (U.S.A.), 1968 revision, asreproduced, e.g., in “The Pharmaceutical Basis of Therapeutics”, 4^(th)edition 1970, eds. Goodman and Gilman (The Macmillan Company). Forconvenience, the relevant data is reproduced below. Recommended DailyDietary Allowance of Pyridoxine Age in Years (except for Infants) Amount(mg) Infants up to 2 months 0.2  2-6 months 0.3 Children  6-12 months0.4  1-2 0.5  2-3 0.6  3-4 0.7  4-6 0.9  6-8 1.0  8-10 1.2 Males 10-121.4 12-14 1.6 14-18 1.8 18-22 2.0 22-35 2.0 35-55 2.0 55-75+ 2.0 Females10-12 1.4 12-14 1.6 14-18 1.8 16-18 2.0 18-22 2.0 22-35 2.0 35-55 2.055-75+ 2.0 Pregnancy 2.5 Lactation 2.5

In accordance with a preferred embodiment of the invention, a method ofreducing the risk of an epileptic occurrence in a high-risk humansubject comprises the step of administering to the subject at least onesubstance selected from pyridoxal, pyridoxamine and pyridoxine, theirpharmaceutically acceptable functional derivatives and salts of any ofthese substances, in an amount which is equivalent to from about 2 toabout 500 times the recommended daily dietary allowance of pyridoxine.

The high-risk human subject may be, e.g., a pregnant or lactating womanwith a family history of seizure disorders; a child with a familyhistory of seizure disorders, particularly such a child within the agerange of about 1-5 years, and then at puberty period 11-15; a child witha personal history of seizure episodes such as febrile, orbreath-holding convulsions; a child with a congenital injury orasphyxia, particularly within the age of childhood or adolescence. Thehigh-risk human subject may alternatively be, e.g. a person who hasendured brain trauma, in which case pyridoxine is preferablyadministered in the amounts described above for a period of about 1-2years after the episode. In another preferred embodiment of theinvention, the high-risk human subject is one who had in the pastundergone a course of treatment with at least one AED, which course oftreatment has since been terminated. In such a case the course ofadministration of pyridoxine is preferably continued over a time periodof about 1-2 years in a dosage 2-20 mg/kg, preferably 4-10 mg/kg.Preferably, the course of administration of pyridoxine is commencedimmediately following termination of the course of AED treatment.

It is important to note that several specific forms of epilepsy, such asabsence seizures, atypical absences and atonic seizures [ILAE revisedclassification of epileptic seizures (1981)] were shown not to besuitable for pyridoxine treatment.

In accordance with another preferred embodiment of the invention, amethod of reducing the risk of epileptic attacks and alleviatingepileptic occurrences, as well as alleviating the side effects of AEDsin a human subject, comprises the step of administering to the subjectdiagnosed as an epileptic patient, at least one substance selected fromthe group consisting of pyridoxal, pyridoxamine and pyridoxine, theirpharmaceutically acceptable functional derivatives and salts of any ofthese substances, in an amount which is equivalent to from about 2 toabout 500 times the recommended daily dietary allowance of pyridoxine,but does not exceed 500 mg of pyridoxine daily. In this embodiment ofthe invention, there is preferably co-administered with said at leastone substance, at least one antiepileptic drug (AED), such as, by way ofan example, at least one such drug selected from phenytoin or otherhydantoins; phenobarbital or other barbiturates, primidone,carbamazepine and oxacarbamazepine, valproic acid or its derivatives;oxazolidines; benzo-diazepines; felbamate, gabapentin, lamotrigine,vigabatrin, adrenocorticotropic hormone (ACTH) (“Antiepileptic Drugs”,4^(th) Edition, Ed. by R. Levy, R. H. Mattson, B. S. Meldrum; RavenPress, NY, N.Y., 1995), as well as any other AED in use or potentialAED. Neuroprotective drugs and nootropes, although not known as AEDs,may be used in place of the AEDs in the combination referred to above.

In accordance with a preferred embodiment of the invention, a method ofpreventing epileptic episodes and alleviating both epileptic episodes aswell as the side effects of AEDs comprises the step of administering tothe subject:

-   -   (a) at least one substance selected from the group consisting of        pyridoxal, pyridoxamine and pyridoxine, their pharmaceutically        acceptable functional derivatives and salts of any of these        substances, in an amount which is equivalent to from about 2 to        about 500 times the recommended daily dietary allowance of        pyridoxine; in combination with    -   (b) at least one AED, which may be selected from among those        specified above.

In this embodiment of the invention, the human subject may be one whohas to undergo a course of treatment with at least one AED and is atperiod of cancellation of AED treatment. Under these conditions theamount of AED administered daily in combination with vitamin B6 (orderivative thereof, as specified above) is preferably about 10-90% lessthan the amount of AED administered daily in the absence of vitamin B6or a derivative thereof.

It will be appreciated that in those embodiments of the invention, inwhich an AED is co-administered with the at least one substance selectedfrom pyridoxal, pyridoxamine and pyridoxine, their pharmaceuticallyacceptable functional derivatives and salts of any of these substances,then co-administration may take the form of separate administration ofthe two components. However, it will generally be more convenient toco-administer the two components in the form of an integratedcomposition as a tablet, capsule, dragee, or syrup or any otherformulation.

Thus, there is provided in accordance with another preferred embodimentof the invention a pharmaceutical composition which comprises a mixture,preferably an admixture, of:

-   -   (a) at least one substance selected from pyridoxal, pyridoxamine        and pyridoxine, their pharmaceutically acceptable functional        derivatives and salts of any of these substances;    -   (b) at least one AED, neuroprotective drug or nootrope compound;        and    -   (c) at least one carrier, diluent or excipient.

In a preferred embodiment of the invention, the mixture or admixture,and/or the individual components thereof, may be microencapsulated,using conventional microencapsulation techniques, such as are disclosedin U.S. Pat. No. 6,156,347, the contents of which are incorporatedherein by reference. Liposomes may also be employed formicroencapsulation for the admixture or components thereof, as is knownin the art. The carriers, diluents or excipients are those known in thepharmaceutical art, and will be selected, as is well known in that art,according to the relevant mode of administration, whether this be e.g.oral, parenteral, intranasal, rectal, transdermal or other acceptablemode of administration.

In the pharmaceutical compositions of the invention, the weight ratio of(a):(b) preferably lies in the range of about 1:0.1 up to about 1:1,starting of 1:0.1 at the beginning of treatment, from which time thedose of AED is gradually increased, if necessary, up to a stabilizedratio of about 1:1. Following a period of administration of (a) and (b)in a ratio of about 1:1, over the period of cancellation of treatment,the dose of (b) is gradually decreased and the ratio of (a):(b) iscommensurately gradually altered from about 1:1 to about 1:0.1, wherebyto gradually result in full replacement of (b) by (a), when the dose of(b) becomes equal to 0. These compositions will desirably be in the formof dosage units, which contain in total no more than the safe maximumadult daily dose of each of the components (a) and (b), preferablycontaining no more than about 500 mg of component (a), and no more thanthe typical adult daily dose of component (b).

It will be apparent to those skilled in the art that, insofar as, on theone hand, the invention relates to methods of treatment of individuals(including e infants and children), for whom the daily adult dose wouldbe unsuitable, and on the other hand, the daily dose for adults andchildren may in any event be administered in divided doses, the dosageunits of the invention may contain a fraction of the typical adult dailydose of component (b) and a fraction of the maximal daily dose ofcomponent (a). At least one AED may be, for example, selected fromphenytoin or other hydantoins; phenobarbital or other barbiturates,primidone, carbamazepine and oxacarbamazepine, valproic acid or itsderivatives; oxazolidines; benzodiazepines; felbamate, gabapentin,lamotrigine, vigabatrin, adrenocorticotropic hormone (ACTH),(“Antiepileptic Drugs”, 4^(th) Edition, Ed. by R. Levy, R. H. Mattson,B. S. Meldrum; Raven Press, NY, N.Y., 1995), as well as any other AED inuse or potential AED. Neuroprotective compounds and nootropes, althoughnot known as AEDs, may also be used as a component (b).

Insofar as reference has been made above to the typical adult daily doseof component (b) of the pharmaceutical compositions of the invention, itwill be convenient to reproduce such data in respect of certain knownAED (Antiepileptic Drugs 4^(th) Ed. Ed. R. Levy, R. H. Mattson, B. S.Meldrum). It must be stressed, however, that the embodiments of thepresent invention that require the utilization of a known AED mayequally utilize such drugs, which are not specified or tabulated herein,including potential AEDs, neuroprotective compounds or nootropes.Typical Adult Daily Dose Of Some Known Anticonvulsant Drugs Daily DosageName of Drug (mg/kg) Carbamazepine  5-20 Valproic acid 10-20 Phenytoin4-7 Zonizamide  8-12 Clonazepam 10-40

Hence, the present invention provides a new class of compositions, whichreduce the risk of epileptic attacks and/or alleviate them, as well asreduce side effects of AEDs. The compositions of the present inventionare characterized by the inclusion of a nontoxic component withneuroprotective and anticonvulsive properties, thus greatly reducing thechance of side effects. The activity of the compositions is sufficientso that they are as effective at relatively lower dosage levels thanconventional anticonvulsants.

It should be noted that treatment of the type of epilepsy known as“pyridoxine-dependent epilepsy” by administration of pyridoxine has beenreported in the art (Hunt et al. Pediatrics 1954; 13:140; Rosenberg In:Medical Genetics McKusic V A, ed. 1995: 73-8; Shideler Am. J. Med.Technol. 1983; 49:17-22; Scriver and Hutchison Pediatrics 1963;31:240-50). The literature also suggests that medicinal method oftreating pyridoxine-dependent epilepsy is unsuitable for the treatmentof other forms of epilepsy. The present invention, in contrast, providespyridoxine alone to be suitable for use in the prevention and treatmentof initial forms of the disease as well as for prevention of relapse offorms of epilepsy other than pyridoxine-dependent epilepsy. Inaccordance with the invention, there is provided pyridoxine incombination with AEDs, either as a mixture or chemically bondedmoieties, for the medicinal treatment of other than pyridoxine-dependenttypes of epilepsies at different stages of the disease. However, itshould be noted that some specific forms of epilepsy, e.g. absenceseizures, atypical absences and atonic seizures, which are unsuitablefor pyridoxine treatment are also unsuitable for treatment bycombinations of pyridoxine and AEDs either as mixtures or as chemicallybounded moieties.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the scores of PTZ-induced convulsive reactions ingenetically epilepsy-prone (EP) mice treated with either NC-001, vitaminB6, GABA, or a combination of vitamin B6 and GABA, as indicated.

FIG. 2 depicts the PTZ-induced convulsive response in geneticallyepilepsy-prone (EP) BALB/c mice treated with 5 mg/kg, 7.5 mg/kg or 10mg/kg NC-001.

FIG. 3 depicts the anti-convulsive effects of NC-001 administered orallyto genetically epilepsy-prone (EP) mice.

BEST MODE FOR CARRYING OUT THE INVENTION

In accordance with the present invention a class of compounds is setforth for reducing the risk of epileptic occurrences, for alleviatingepileptic occurrences and reducing side effects of AED as well. Inaccordance with a preferred embodiment of the present invention, thecompositions are compounds, which comprise (a) a vitamin B6 moiety, and(b) an AED moiety. The vitamin B6 moiety is linked chemically to theAED, neuroprotective or neurotransmitter compounds, or nootropes to givea new AED compound, which may be represented by the formula:

wherein R′ represents the AED moiety and R is selected from the groupconsisting of —CH₂H, —CHO and CH₂NH₂, the composition being employed ina dosage no greater than its maximum safe dosage.

The AED moiety can be virtually any AED (or other compounds enlisted)which can be linked to the vitamin B6 moiety via attachment byetherification or the like to the —CH₂OH or —OH groups attached to thepyridine nucleus of the vitamin B6 moiety. Without limitation and by wayof illustration and example, the AED moiety may be one which is obtainedby reacting any AED of phenytoin or other hydantoins; phenobarbital orother barbiturates, primidone, carbamazepine and oxacarbamazepine,valproic acid or its derivatives; oxazolidines; benzo-diazepines;felbamate, gabapentin, lamotrigine, vigabatrin, adrenocorticotropichormone (ACTH), (“Antiepileptic Drugs”, 4^(th) Edition, Ed. by R Levy,R. H. Mattson, B. S. Meldrum; Raven Press, NY, N.Y., 1995), as well asany other AED in use or potential AED with the aforementioned —CH₂OHgroup of vitamin B6. Neurotransmitters, neuroprotective compounds andnootropes, although not known as AED, may be used in place of the AEDsin the combination referred to above.

Thus, the preferred dosage range of the chemically coupled vitamin B6moiety and the AED moiety is limited to no more than the safe maximumdaily dose of each of the components. Such daily dose for adults andchildren may be administrated in the divided doses. It is advisable tostay within these ranges since the cited dosages provide significantalleviation of epileptic convulsions and/or serve to significantlyreduce the risk of epileptic occurrence. According to the data obtained,chemically coupled vitamin B6 moiety with other anticonvulsive (orneuroprotective, neurotransmitter, nootrope) moieties are effective inlow enough dosages so that adverse side effects are minimized oreliminated.

Without wishing to be bound by any particular theory, it is believedthat most of AEDs as are set forth above, and other AED as well, passthrough the blood-brain barrier in only small proportions, when presentin the blood stream, and thus relatively high amounts of these compoundsare needed in the blood stream to provide an effective amount of the AEDwithin the brain. It is surmised that since vitamin B6 is easilyabsorbed into the gastrointestinal tract and passes relatively readilythrough the blood-brain barrier, by chemically linking AED and vitaminB6 moieties, the AED moieties will be more readily absorbed and carriedacross the blood-brain barrier, and thus a lower concentration of AED inthe bloodstream will be required to reach an efficacious concentrationof AED in the brain. This provides effective treatment for seizuredisorders with less, or without the deleterious side effects, many ofwhich are brought about by high concentrations of AED in the bloodstream.

In accordance with another preferred embodiment of the presentinvention, vitamin B6 and anticonvulsant compounds can be administeredseparately or in physical mixtures to a patient in such a manner thatboth are presented to the subject at the same time. Preferably, thevitamin B6 and AED compounds are supplied in a single formulation.Preferred weight ratios of vitamin B6 to AED range from about 0.1:1during dose-titration period at the beginning of treatment, up to about1:1 when the treatment regime is stabilized. A gradual increase in theweight ratios of vitamin B6 to AED down to about 1.0:0.1 is recommendedover the period of treatment cancellation, which is preferably ended bylong-term treatment with pyridoxine alone.

The vitamin B6 compound has the formula:

wherein R is selected from the group consisting of —CH₂OH, —CHO and—CH₂NH₂. The AED may be, for example, phenytoin or other hydantoins;phenobarbital or other barbiturates, primidone, carbamazepine andoxacarbamazepine, valproic acid or its derivatives; oxazolidines;benzodiazepines; felbamate, gabapentin, lamotrigine, vigabatrin, oradreno-corticotropic hormone (ACTH), or other AED. Neuroprotective orneurotransmitter compounds and nootropes, although not known as AEDs,may be used in place of the AEDs in the combination referred to above.

A more preferred range for the amount of the vitamin B6 compound is fromabout 2 mg to about 10 mg of vitamin B6 per kg body weight per day, andno more than the maximum daily doses allowable of each AED. The dailydose for adults and children may be administrated in the divided doses.It is very advisable to stay within these ranges since the cited dosagesprovide significant alleviation of epileptic seizures and/or serve tosignificantly reduce the risk of epileptic occurrence. Use of mixtureswith pyridoxine allows decreasing doses of AED which are included intoadmixture, so that adverse side effects are minimized or eliminated.

The present invention will be better understood by reference to theillustrative examples, which follow wherein synthesis of a number ofcompounds in accordance with the present invention is set forth.

EXAMPLES

The synthesis protocols for conjugates of vitamin B6 with γ-aminobutyricacid (GABA), with kynurenic acid and with both GABA and kynurenic acidare exemplified below in Examples 1-3. However, it should be understoodthat similar procedures are also applicable for covalently linkingpyridoxine or its derivatives to other natural or non-naturalbiologically active acids, e.g. anti-epileptic drugs or otherneuroprotective compounds and nootropes, natural or syntheticneurotransmitters etc. For example, anti-epileptic drugs such asvalproic acid, 1-(aminomethyl)cyclohexaneacetic acid (gabapentin) and4-Amino-5-hexenoic acid (vigabactrin) may be chemically linked topyridoxine by similar synthesis procedures as described in Examples 1 to3. The end product is an ester such as, for example, the ester ofvalproic acid and vitamin B6 derivative shown below:

Ester of valproic acid and vitamin B6 derivative.

Other biologically active molecules, for example (amino-) anti-epilepticdrugs such as 5-Ethyl-5-phenyl-2,4,6(1H,3H,5H)-pyrimidinetrione(Phenobarbital); 5,5-Diphenyl-2,4-imidazolidinedione (Phenyloin);5-Ethyldihydro-5-phenyl-4,6(1H,5H) pirimidinedione (Primidone);5H-Dibenz[b,f]azepine (Carbamazepine); 2-Phenyl-1,3-propanedioldicarbamate (Felbamate) etc. may also be chemically linked topyridoxine. The procedure of synthesis of these molecules includes threestages as detailed below:

1. Synthesis of 5-Bromomethyl-3-hydroxy-4-hydroxymethyl-2-methylpyridinehydrobromide (3) as shown below in Example 1, step 2.

2. Synthesis of Li-amino-derivatives as shown below:

R—NH+BuLi→R—NLi+BuH

Wherein R—NH represents an anti-epileptic drug having an amino group.

A reaction wherein the R—NH drug is Phenyloin is exemplified below:

3. Synthesis of pyridoxine-(amino-) drug conjugate:

Example 1 Synthesis of[5-Hydroxy-6-methyl-4-(hydroxymethyl)-pyrid-3-yl]methyl-4-aminobutyrate,dihydrochloride (=B6-GABA)

The chemical structure of[5-Hydroxy-6-methyl-4-(hydroxymethyl)-pyrid-3-yl]methyl-4-aminobutyrate,dihydrochloride is:

Synthesis of[5-Hydroxy-6-methyl-4-(hydroxymethyl)-pyridl-3-yl]methyl-4-aminobutyrate,dihydrochloride is a five-stage procedure. All synthesized compoundswere characterized by NMR and mass spectroscopy analyses.

1. Synthesis of 3,4-Bis(bromomethyl)-5-hydroxy-6-methylpyridine (2).

In the first stage Pyridoxine (1) (20 g, 0.097 mol) was refluxed in 48%hydrobromic acid (150 ml) for a 1 h. After crystallization at −15° C.the precipitate was separated, washed with acetone and dried. The yieldwas 25 g (68%). MS (ES): m/z 295.95; 297.93 (M+H)⁺.

2. Synthesis of 3-Bromomethyl-5-hydroxy-4-hydroxymethyl-6-methylpyridinehydrobromide (3)

4,5-Bis(bromomethyl)-3-hydroxy-2-methylpyridine (2) (3 g, 0.008 mol) wasstirred in water (24 ml) at 45-50° C. for 40 min. The solution wasfiltered and evaporated under vacuum. The obtained residue wascrystallized from ethanol. The yield was 1.2 g (50%). The position ofbromomethyl- in pyridine-ring was verified by qualitative analysis with2,6-dichloroquinone-4-chloroimide (Harris and Folkers (1939) J. Am.Chem. Soc. 61: 247). M.p. 158-159° C.

¹H NMR (CD₃OD), δ: 2.62 (s., 3H), 4.72 (s., 2H), 5.18 (s., 2H), 8.30(s., 1H). MS (ES): m/z 231.92; 233.91 (M+H)⁺.

3. Synthesis of 4-(tert.) Buthyloxycarbonylaminobutiric acid (Boc-GABA)

NH₂(CH₂)₃COOH+Boc₂O→Boc-NH—(CH₂)₃COOH  (4)

Where Boc₂O=[CO₂C(CH₃)₃]₂O

4-aminobutiric acid (GABA) (5.15 g, 0.05 mol) in 100 ml solution ofwater: 1N NaOH (1:1 v/v) was stirred in an ice-water bath.Di-tert.-butyl pyrocarbonate (11.99 g, 0.055 mol) was added at sametemperature. The reaction mixture was stirred at room temperature for 1hour. The solution was concentrated under vacuum to about 70 ml andcooled in an ice-water bath, covered with a layer of ethyl acetate (100ml). Then it was acidified with a dilute solution of KHSO₄ to pH 2-3.The aqueous phase was extracted with ethyl acetate (2×50 ml). Ethylacetate extracts were pooled, washed with water (2×70 ml), dried overanhydrous Na₂SO₄ and evaporated under vacuum. The yield was 10.00 g(98%).

¹H NMR (DMSO-d₆) δ: 1.37 (s., 9H), 1.60 (m., 2H), 2.19 (t., 2H), 2.92(t., 2H). MS (ES): m/z 202.08 (M−H)³¹ .

4. Synthesis of[5-Hydroxy-6-methyl-4-(hydroxymethyl)-pyrid-3-yl]methyl-4-aminobutyrate

4-(tert.) buthyloxycarbonylaminobutiric acid (4) (2.03 g, 0.01 mol) andcesium carbonate (4.89 g., 0.015 mol) were stirred into dry DMSO (50 ml)at room temperature for 1.5 h under argon.3-Bromomethyl-5-hydroxy-4-hydroxymethyl-6-methylpyridine hydrobromide(3) was added to the reaction mixture. The resulting brown solution waskept for 18 h. at room temperature. The next day the solution wasdiluted with water (150 ml) and extracted with ethyl acetate (3×50 ml).Ethyl acetate extracts were pooled, washed with water (3×50 ml), driedover anhydrous Na₂SO₄ and evaporated under vacuum. The crude precipitatewas purified by column chromatography on silica gel with gradient.Eluent: chloroform (100%), chloroform:ethyl acetate (50%:50%), ethylacetate (100%). The yield was 1.0 g (28%).

¹H NMR (DMSO-d₆) δ: 1.34 (s., 9H), 1.60 (m., 2H), 2.29 (t., 2H), 2.32(s., 3H), 2.88 (t., 2H), 4.66 (s., 2H), 5.08 (s., 2H), 7.87 (s., 1H). MS(ES): m/z 355.28 (M+H)⁺.

5. Synthesis of[5-Hydroxy-6-methyl-4-(hydroxymethyl)-pyrid-3-yl]methyl-4-aminobutyrate,dihydrochloride (6)

The solution of 5N HCl in ethyl acetate (7 ml) was added to solution of[5-Hydroxy-6-methyl-4-(hydroxymethyl)-pyrid-3-yl]methyl-4-aminobutyrate(5) (1.8 g, 5.08 mmol) in ethyl acetate (20 ml) at 0° C. The reactionmixture was stirred at 0-5° C. for 2 hours. Residual compound wasseparated and crystallized from the mixture of methanol-ether. The yieldwas 0.7 g. (42%).

¹H NMR (CD₃OD) δ: 1.95 (m., 2H), 2.64 (t., 2H), 2.65 (s., 3H), 2.99 (t.,2H), 5.09 (s., 2H), 5.38 (s., 2H), 8.22 (s., 1H). MS (ES): m/z 255.13(M+H)⁺.

Example 2 Synthesis of[3-(5-Hydroxy-6-methyl-4-(hydroxymethyl)pyrid-yl]methyl-2-[(4-hydroxy)quinoline]carboxylate(=B6-Kyn)

The chemical structure of[3-(5-Hydroxy-6-methyl-4-(hydroxymethyl)pyrid-yl]methyl-2-[(4-hydroxy)quinoline]carboxylateis:

A mixture of 4-hydroxyquinoline-2-carboxylic acid hydrate (kynurenicacid (7)) (1.80 g, 8.70 mmol) and cesium carbonate (4.25 g, 13.05 mmol)were stirred in dried DMSO (70 ml) at room temperature for 1.5 h underargon. Followed by addition of3-Bromomethyl-5-hydroxy-4-hydroxymethyl-6-methylpyridine hydrobromide(3) (3.58 g, 11.42 mmol). The obtained brown solution was kept for 18 hat room temperature, then diluted with water (200 ml) and extracted withethyl acetate (12×150 ml). After crystallization at 5° C. theprecipitate was separated, washed with ethyl acetate, ether and dried.The yield was 0.25 g. (7.8%).

¹H NMR (DMSO-d₆) δ 2.36 (s, 3H), 4.77 (s, 2H), 5.47 (s, 2H), 6.60 (s,1H), 7.37 (t, 1H), 7.69 (t, 1H), 7.89 (d, 1H), 8.05 (s, 1H), 8.06 (d,1H).MS (ES): m/z 341.17 (M+H)⁺.

Example 3 Synthesis of5-Hydroxy-4-hydroxymethyl-6-methyl-pyrid-3-yl)methyl[4-(4-hydroxyquinoline-2-carbonylamino)]butyrate (B6-GABA-Kyn)

The chemical structure of3-Hydroxy-4-hydroxymethyl-2-methyl-pyrid-5-yl)methyl[4-(4-hydroxyquinoline-2-carbonylamino)]butyrate is:

1. Synthesis of 4-(4-Hydroxyqunoline-2-carbonylamino)butanoic acid (10).BSA (N,O-bis(trimethylsilyl)acetamide) (3.26 ml, 13.20 mmol) was addedto a suspension of 4-aminobutanoic acid (GABA) (0.62 g, 6.00 mmol) indry dichloromethane (10 ml) and the mixture was stirred for 6 hours at50° C. The resulting solution was added to a mixed anhydride preparedfrom kynurenic acid (7) (0.95 g, 5.00 mmol), Et₃ N (1 ml), EtOCOCl (0.5ml, 5.25 mmol) in dry DMF (10 ml) incubated at −20° C. for 20 min. Thereaction mixture was stirred at −5° C. for 2 hours and kept at 4° C. forfurther 18 hours. Water (50 ml) and ethyl acetate (30 ml) were thenadded. The compound (10) in mixture with kynurenic acid was separatedfrom the water layer (0.5 g).

¹H NMR (DMSO-d₆) δ 1.79 (m, 2H), 2.28 (t, 2H), 6.67 (s, 1H), 7.33 (t,1H), 7.67 (t, 1H), 7.91 (d, 1H), 8.05 (d, 1H), 9.00 (s, 1H), 11.78 (s,1H); m/z 273.06 (M−H)⁻.

2. Synthesis of 5-Hydroxy-4-hydroxymethyl-6-methyl-pyrid-3-yl)methyl[4-(4-hydroxyquinoline-2-carbonylamino)]butyrate (11)

The mixture of compound (10) (0.47 g, 1.71 mmol) and cesium carbonate(0.89 g, 2.74 mmol) was stirred for 1.5 hours in dried DMSO_(40 ml) atroom temperature under argon. Compound (3) (0.72 g, 2.30 mmol) was thenadded. The resulting brown solution was kept for 18 hours at roomtemperature, before being diluted with water (120 ml) and extracted withethyl acetate (5×100 ml). After crystallization at 5° C. the precipitatewas separated, washed with ethyl acetate, ether and dried. The yield was0.04 g.

¹H NMR (DMSO-d₆) δ: 1.82 (m, 2H), 2.48 (s, 3H), 2.50 (t, 2H), 4.79 (s,2H), 5.28 (s, 2H), 6.79 (s, 1H), 7.37 (t, 1H), 7.69 (t, 1H), 7.93 (d,1H), 8.05 (s, 1H), 8.06 (d, 1H); 9.03 (s, 1H); m/z 424.08 (M−H)⁻.

Example 4 Anticonvulsive effect of Pyridoxine Chemically Linked withGABA (NC-001 Compound)

Anticonvulsive effect of Pyridoxine chemically linked with GABA,[5-hydroxy-6-methyl-4-(hydroxymethyl)-pyrid-3-yl]methyl-4-aminobutyrate,dihydrochloride (=B6-GABA conjugate; also referred to as NC-001compound), was examined in an animal model of genetic epilepsy.

The animal model used is epilepsy-prone (EP) subline of mice that wasselectively bred from a strain of BALB/c mice (Dolina et al. inEpilepsia (1993) 43: 33-42). EP mice are characterized as havinggenetically increased susceptibility to seizures.

EP mice were subjected to seizure induction by intraperitoneal (i.p.)injection of pentylenetetrazol (PTZ) 50-60 mg/kg dissolved in saline.The EP animals were i.p. treated with the tested compound(s) 10 to 60minutes prior to the PTZ injection.

The tested compounds were the following:

-   1) NC-001 10 mg/kg-   2) Pyridoxine hydrochloride (=Vitamin B6) 10 mg/kg-   3) GABA 10 mg/kg-   4) Separately injected Vitamin B6 and GABA, 10 mg/kg each.    A group of EP animals injected with PTZ only, with no further    treatment, served as a control group.

The intensity of the PTZ-induced convulsive reaction for each group wasevaluated in scores according to the following scale:

Intensity of PTZ-induced Convulsive Reaction in Scores

-   1. A few myoclonic jerks (less than 10)-   2. Less than 20 jerks-   3. Less than 30 jerks-   4. 30-40 jerks/jerks and jumps/short partial convulsions.-   5. Uninterrupted jerks/series of jerks and jumps/repeated partial    convulsions-   5.5 Abortive generalized convulsions-   6. Single generalized convulsive attack-   7. Series of jerks, jumps & single generalized convulsive attack;    single generalized convulsions with further motor excitation-   7.5 Severe prolonged generalized convulsions-   8. Repeated generalized convulsions-   9. Series of jerks/jumps & repeated convulsions-   10. Status epilepticus-   12. Lethal convulsions

In each group of EP animals, convulsive reactions were recorded duringthe first 30 minutes following administration of the seizure inducer.

As shown in FIG. 1, the conjugated compound, NC-001, that was injected30 minutes prior to the PTZ injection, provided almost a completeprotection against the convulsive symptoms. Four out of the six testedmice did not show any convulsive reaction, while the other two animalshad only few convulsive jerks. Under the same experimental setting, GABAalone, as well as GABA and Vitamin B6 injected simultaneously ascombination of both, did not show any anticonvulsive effect at thetested dose of 10 mg/kg. Vitamin B6 by itself showed some protectionagainst PTZ-induced generalized convulsions.

Example 5 The Anticonvulsive Effect of NC-001 is Dose Dependent

In order to further characterize the anticonvulsive activity of thecompounds of the invention, different doses of NC-001, namely pyridoxinechemically linked with GABA were examined.

Genetically epilepsy-prone (EP) BALB/c mice, 3-5 animals in a group,were i.p. administered with either 5 mg/kg, 7.5 mg/kg or 10 mg/kg ofNC-001 thirty minutes prior to i.p. injection of PTZ (60 mg/kg). Thenumbers of seizures were then recorded for each animal during 30 minutesfollowing the PTZ injection. The intensity of convulsive reaction wasscored for each of the treatment groups.

As can be seen in FIG. 2, the NC-001 compound demonstrated adose-dependent anti-convulsive protective effect. Five mg/kgintraperitoneally (i.p.) injected NC-001 already induced protectiveeffect; only two of the four EP mice treated with this compoundexhibited generalized convulsions, while the other two animals had anumber of jerks. At a dosage of 7.5 mg/kg, NC-001 prevented generalizedPTZ-induced convulsions in all three treated EP mice, though numerousjerks were observed in all of them. NC-001 injected at a dose of 10mg/kg, completely prevented generalized convulsive reactions, whilesingle jerks occurred in one of EP mice.

Conclusion: NC-001 effectively protects genetically epilepsy-proneanimals, which are characterized by enhanced seizure predisposition,from PTZ-induced convulsions. The anticonvulsive effect is dosedependent.

Example 6 The NC-001 Compound Demonstrated Anti-Convulsive Effect whenOrally Administered

In order to test the ability of the vitamin B6-GABA conjugated compoundto cross the GI barrier, epilepsy-prone (EP) mice were orallyadministered with NC-001.

A group of 12 female EP mice were i.p. treated with 50 mg/kg PTZ toinduce seizures. Thirty minutes prior to PTZ administration, NC-001 atthe dose of 30 mg/kg was orally administered to four of the animals(=treated group), the other eight animals were treated with vehicle onlyand served as a control group. All twelve animals were scored, during 30minutes following i.p. PTZ administration, for intensity of convulsivereactions (see table of convulsive reaction scores as appear above inExample 4).

As can be seen in FIG. 3, a significant protective effect wasdemonstrated in the EP mice orally administered with the NC-001compound.

Example 7 Physical Admixture of AED with Pyridoxine and Testing Thereof

A physical admixture of (a) pyridoxine hydrochloride and (b) an AED isprepared. It is administered simultaneously or substantiallysimultaneously to patients suffering from epilepsy. The weight ratio of(a):(b) is in the range of about 0.1:1 to 1:1 near the beginning oftreatment and 1:0.1 near the end of treatment. These compositions willdesirably be in the form of dosage units, which contain in total no morethan the safe maximum adult daily dose of each of the components (a) and(b), preferably containing no more than about 500 mg of component (a) ata daily dose 2-10 mg/kg, particularly 4-7 mg/kg, and no more than thetypical adult daily dose of component (b).

The admixture reduces the risk of epileptic occurrence or alleviatesepileptic occurrence and diminishes of AED toxicity. An admixture may beadministered in the form of tablets, capsules, syrups, microcapsules,liposomes, or any other pharmaceutically acceptable forms.

Example 8 Pyridoxine-Supplemented Phenyloin as an Example ofCo-Administration of AED with Pyridoxine

Phenyloin (PHT) is prescribed for medication of generalizedtonic-chronic generalized convulsions, complex partial seizures andsimple partial seizures. The efficacy of the mixtures in accordance withpresent invention was demonstrated in the animal model of geneticepilepsy—audiogenic sensitive rats, which reacted with generalizedconvulsions to sound-stimulation. In the experiments, intensity of 100db sound stimulation was used.

The seizure sensitivity to the sound stimulation was tested in twogroups of audiogenic sensitive rats chronically treated with PHT. Onegroup of rats was long-term treated with pyridoxine (75 mg/kg indrinking water). The second group included pyridoxine-untreated rats.The initial injection of PHT 75 mg/kg was followed by 12 successiveinjections of PHT 50 mg/kg once a day. Eleven rats were used in eachgroup. The incidence and intensity of sound-induced convulsions werecomparatively estimated in both groups of rats at the 13^(th) and14^(th) days, so that each of animals was tested twice.

The experiments showed that only two of 22 tests (9%) resulted insound-induced convulsions in the group of pyridoxine-treated EP rats,while 6 convulsive reactions (27.3%) were obtained in the group ofanimals treated with PHT only (pyridoxine untreated animals). Moreover,under same dosage of PHT given chronically, the intensity ofsound-induced convulsions estimated in scores was significantly lower inthe pyridoxine-treated animals in comparison to the untreated EP-rats.Hence, it was shown that co-administration of high-dose pyridoxinesignificantly increased the efficacy of chronic PHT administration inepileptic animals.

Example 9 Reduction of PHT Toxicity by Co-Administration of Pyridoxine

Sacrificed animals of both the pyridoxine-treated and untreated groupsdescribed in Example 8 were examined. The signs of PHT toxicity such asa compressed liver, bleeding areas in the lungs and enlarged adrenalswere found in all 11 EP-rats chronically treated with PHT alone, but notin those which were given the same dose of PHT co-administrated withpyridoxine (75 mg/l in drinking water). Hence, co-administration ofpyridoxine reduced the toxicity of PHT given chronically over the periodof 12 days at the dosage 50 mg daily following the initial injection atthe dose 75 mg/kg.

Example 10 Use of Compositions

The compositions of each of above-described Examples are utilized in adosage no greater than the maximum safe dosage for the individualcomponents to treat patients to alleviate and retard epilepticconvulsions. At this concentration range each of the compositions showssignificant activity in retardation and alleviation of epilepsy.

The above examples illustrate the synthesis and efficacy of variouscompositions in accordance with the present invention.

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodification, and this application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from thepresent disclosure as come within known or customary practice in the artto which the invention pertains and as may be applied to the essentialfeatures herein before set forth.

1. A compound of the general formula (I):

wherein R′ represents an anti-epileptic drug, anticonvulsive drug,neuroprotective drug, neurotransmitter or nootrope moiety; R is selectedfrom the group consisting of —CH₂OH, —CHO and —CH₂NH₂; andpharmaceutically acceptable salts thereof.
 2. The compound according toclaim 1, wherein R′ is an anti-epileptic drug moiety.
 3. The compoundaccording to claim 2, wherein said anti-epileptic drug is selected fromthe group consisting of phenytoin and other hydantoins; phenobarbitaland other barbiturates, primidone, carbamazepine and oxacarbamazepine,valproic acid or its derivatives; oxazolidines; benzo-diazepines;felbamate, gabapentin, lamotrigine, vigabatrin and adrenocorticotropichormone (ACTH).
 4. The compound according to claim 1, wherein R′represents a moiety of y-aminobutyric acid and/or kynurenic acid.
 5. Acomposition comprising a physical mixture of: (a) at least one substanceselected from the group consisting of pyridoxal, pyridoxamine andpyridoxine, their pharmaceutically acceptable functional derivatives andsalts thereof; and (b) at least one anti-epileptic drug, anticonvulsivedrug, neuroprotective drug or nootrope compound.
 6. The compositionaccording to claim 5, wherein component (b) is an anti-epileptic drug.7. The composition according to claim 6, wherein said anti-epilepticdrug is selected from the group consisting phenytoin of and otherhydantoins; phenobarbital and other barbiturates, primidone,carbamazepine and oxacarbamazepine, valproic acid or its derivatives;oxazolidines; benzo-diazepines; felbamate, gabapentin, lamotrigine,vigabatrin and adrenocorticotropic hormone (ACTH).
 8. A pharmaceuticalcomposition comprising a therapeutically effective amount of thecompound of the general formula (I)

and a pharmaceutically acceptable carrier or excipient, wherein R′represents an anti-epileptic drug, anticonvulsive drug, neuroprotectivedrug, neurotransmitter or nootrope moiety; and R is selected from thegroup consisting of —CH₂OH, —CHO and —CH₂NH₂; and pharmaceuticallyacceptable salts thereof.
 9. The pharmaceutical composition according toclaim 8, wherein the compound of the general formula (I) having R′ in anamount which is no greater than the maximal safe amount for a singleadministration of the attached anti-epileptic drug, anticonvulsive drug,neuroprotective drug, neurotransmitter or nootrope component.
 10. Apharmaceutical composition comprising therapeutically effective amountsof components (a) and (b) as defined above in claim 5, and at least onepharmaceutically acceptable carrier, diluent, or excipient.
 11. Thepharmaceutical composition according to claim 10, wherein components (a)and (b) are present in dosages no greater than their respective maximalsafe dosages for a single administration.
 12. A method of treatment of aneurological disease or disorder comprising administering to anindividual in need thereof a therapeutically effective amount of acompound of the general formula (I):

wherein R′ represents an anti-epileptic drug, anticonvulsive drug,neuroprotective drug, neurotransmitter or nootrope moiety; and R isselected from the group consisting of —CH₂OH, —CHO and —CH₂NH₂; andpharmaceutically acceptable salts thereof.
 13. A method of treatment ofa neurological disease or disorder comprising administering to anindividual in need thereof a therapeutically effective amount of acomposition in accordance with claim
 5. 14. A method of treatment of aneurological disease or disorder comprising co-administering to anindividual in need thereof a therapeutically effective amounts ofcomponents (a) and (b) as defined in claim 5, in separate compositions.15. The method according to any one of claim 12, wherein saidneurological disease or disorder is epilepsy.
 16. A method forpreventing epileptic episodes, alleviating epileptic episodes and/orreducing side effects of anti-epileptic drugs comprising the step ofadministering to a subject a therapeutically effective amount of acompound of the general formula (I):

wherein R′ represents an anti-epileptic drug, anticonvulsive drug,neuroprotective drug neurotransmitter or nootrope moiety; and R isselected from the group consisting of —CH₂OH, —CHO and —CH₂NH₂; andpharmaceutically acceptable salts thereof.
 17. A method for preventingepileptic episodes, alleviating epileptic episodes and/or reducing sideeffects of anti-epileptic drugs comprising the step of administering toa subject: (a) at least one substance selected from the group consistingof pyridoxal, pyridoxamine and pyridoxine, their pharmaceuticallyacceptable functional derivatives and salts thereof, in an amount whichis equivalent to from about 2 to about 500 times the recommended dailydietary allowance of pyridoxine; in combination with (b) at least oneanti-epileptic drug, anticonvulsive, neuroprotective drug or nootropecompound.
 18. The method according to claim 12, wherein said compound isorally administered.
 19. (canceled)
 20. (canceled)
 21. The method ofclaim 13, wherein said neurological disease or disorder is epilepsy. 22.The method according to claim 13, wherein said composition is orallyadministered.
 23. The method of claim 14, wherein said neurologicaldisease or disorder is epilepsy.
 24. The method of claim 14, whereinsaid compositions are orally administered.